The midbrain dopamine (DA) system is comprised of a diverse group of neurons involved in reward, motivation, cognition and motor control. Recent studies indicate that DA cells may provide a substrate for associative learning suggesting that neuronal plasticity is a significant component of the DA-striatal pathways. The consequences of dopamine dysfunction in this regard are emphasized in pathological conditions that are thought to involve DA, including drug abuse and addiction, schizophrenia, and Parkinson's disease (PD). One of the principal causes of Parkinson's disease, for instance, is a reduction in DA levels due to the death of DA cells in the basal ganglia. In its earliest stages PD is associated with cognitive deficits which precede the onset of motor control dysfunction. We will use a regime of chronic, low dose MPTP treatment as a model of early Parkinson's disease to investigate the behavioral and anatomical effects of DA depletion. Before significant cell loss (in early PD or from low-dose MPTP treatment) cellular and molecular mechanisms work to maintain extracellular DA levels. As a result, there is compensation for the early deficits in cognitive and motor function resulting from an initial DA depletion. The proposed research will use the oculomotor system as a sensitive and quantifiable assay to identify behavioral and cognitive changes produced by depletion of DA. By dissociating motor and cognitive components of visual orienting tasks, we are able to evaluate differential effects of partial DA lesions on these behavioral components. These measures gives us precise control over the effects of MPTP-induced lesions. These experiments will provide important insight into the regulation and plasticity of dopamine neurons by comparing behavioral and cellular consequences of a partial DA lesion at the onset of cognitive and/or motoric dysfunction and after recovery of function resulting from endogenous compensatory mechanisms. The ability to recognize the early behavioral effects of DA depletion and to understand the cellular consequences of this loss will promote the development of treatments for PD which utilize existing cellular and molecular functions while most DA cells are still intact.